10beta-amino-estranes and method for the preparation thereof

ABSTRACT

10B-AMINO-STEROIDS OF THE ESTRANE SERIES AND A METHOD FOR THE PREPARATION THEREOF.

United States Paten 3,567,712 Patented Mar. 2, 1971 ICC US. Cl. 260-239516 Claims ABSTRACT OF THE DISCLOSURE IOB-amino-steroids of the estraneseries and a method for the preparation thereof.

Novel compounds of the present invention include the following:

R is C H hydroxy, 2'-tetrahydropyranyloxy or acyloxy where the acylgroup is derived from a saturated ali-- phatic carboxylic acidcontaining 1 to 10 carbon atoms, a cycloaliphatic acid such ascyclopentylacetic, cyclopentylpropionic or cyclohexylpropionic acid, adicarboxylic acid such as succinic, glutaric or methylsuccinic acid oran aromatic or arylaliphatic acid such as benzoic, salicylic, paminobenzoic, phenylpropionic or phenylacetic acid;

R is hydrogen, lower alkyl, alkyne of the formula C=CRa or alkene of theformula CH=CHRa and wherein Ra is hydrogen or lower alkyl;

R and R or R7 and R together are keto,

R is hydrogen, hydroxy, lower alkyl or halogen such as chlorine orbromine;

R is hydrogen, formyl, acetyl or benzylcarboyl;

R is hydrogen or methyl;

R is hydrogen, methyl, acyl where the acyl group is derived from asaturated aliphatic carboxylic acid containing l to 10 carbon atoms, acycloaliphatic acid such as cyclopentylacetic, cyclopentylpropionic, orcyclohexylpropionic acid, a dicarboxylic acid such as succinic, glutaricor methylsuccinic acid or an aromatic or arylaliphatic acid such asbenzoic, salicylic, p-aminobenzoic, phenylpropionic or phenylacetic acidor COOR 0r -CONHR where R is methyl, ethyl, propyl, butyl, cyclohexyl,phenyl or phenylmethylene;

R is methoxy, ethoxy, morpholino, pyrrolidyl or piperidino;

R is acyloxy where the acyl group is derived from a saturated aliphaticcarboxylic acid containing 1 to 10 carbon atoms, a cycloaliphatic acidsuch as cyclopentylacetic, cyclopentylpropionic or cyclohexylpropionicacid, a dicarboxylic acid such as succinic, glutaric or methylsuccinicacid or an aromatic or arylaliphatic acid such as benzoic, salicylic,p-aminobenzoic, phenylpropionic or phenylacetic acid;

R is hydrogen or lower alkyl;

W is chlorine, bromine, -N NHOCOC H NH or OCOR where R is methyl, ethyl,propyl, butyl, cyclohexyl, phenyl or phenylmethylene;

x, y and t each represent a single or double bond;

2 indicates here and throughout the specification that each of R and Rmay have the a or B configuration and wherein C-5 has the a,configuration when t represents a single bond or when both of x and yrepresent a single bond.

The compounds of the present invention are endowed with androgenic,anabolic, progrestive hypophsial block anesthetic, hypnotic, andsedative activity and are prepared, for example by starting withcompounds of the following formula:

wherein:

R R R R and t have the same meaning set forth hereinbefore and whereinC-S has the a configuration 35 when t represents a single bond.

Scheme I Reaction scheme I illustrates the reaction of a 10;?- carboxycompound or an alkali metal salt thereof (e.g., lithium, sodium orpotassium) with a chlorinating agent such as thionyl chloride, oxalylchloride, PC1 or P001 in a solvent such as an ether (e.g., ethyl etheror isopropyl ether), benzene, toluene, hexane, dimethylformamide to forman acid chloride which, either raw or isolated, is allowed to react withan alkali metal azide, ammonia or hydroxylamino yield the corresponding10;?- carbonylazide, lOfi-carbamoyl or 10fi-hydroxaminic acid (which isthen benzoylated) intermediate which, in a medium such as benzene,water, acetic acid, hydrochloric acid, ether or mixtures thereof,undergoes a Curtius rearrangement to give lOfl-amino-steroids of thefollowing formula:

-w R3 HzT wherein R R R R and thave the same meaning set forthhereinbefore and wherein C-S has the oc configuration when t representsa single bond.

Scheme II Reaction scheme II illustrates the reaction of a 10,8- carboxycompound with ethyl chlorocarbonate in the presence of triethylamine oran acid of the formula RCOOH wherein R is methyl, ethyl, propyl, butyl,cyclohexyl, phenyl or phenylrnethylene in a solvent such as acetone,tetrahydrofurane, dioxane, benzene or dimethyl formamide to yield aLOB-carboxyanhydride compound which either raw or isolated, is allowedto react with an alkali metal azide, NH (not shown) or NH OH and thenbenzoyl chloride (not shown) to give the corresponding intermediatewhich, in a medium such as benzene, toluene or ether undergoes Curtiusrearrangement to yield the 10/3-isocyanato-steroids of the followingformula:

By treatment with hydrochloric acid, acetic acid, water, ether ormixtures thereof, said IOfi-isocyanato-steroids Scheme III R MgBr OH LHzN are converted into IOfl-amino-steroids of the following formula:

wherein R R R R and t have the same meaning set forth hereinbefore andwherein C-S has the a configuration when t represents a single bond.

Starting with these lOfl-amino-5-a-hydrogen-estranes orlOfi-amino-estr-S-enes where R is H or O compounds of the formula:

MIT (if are obtained by Oppenauer reaction wherein R R and R are as setforth hereinbefore, z represents a single or double bond and wherein C-Shas the on configuration when z represents a single bond.

By starting with 10B-amino-estr-4-ene-3,l7-dione and by reacting with asecondary amine such as pyrrolidine, morpholine or piperidine in asolvent such as benzene, toluene, Xylene in the presence of a catalystsuch as ptoluensulfonic acid or the corresponding secondary aminehydrochloride, the corresponding 3-enamine of Formula I is obtained.

Rl U III According to reaction scheme III, after reduction with LiAlHthe enamine of Formula II is split through boiling with a mixture ofacetic acid, sodium acetate and water to form the IOB-amino-testosteroneof Formula III. The reaction of the enamine of Formula I with a Grignardreactant such as methylmagnesium bromide, ethyl magnesium bromide andvinylmagnesium or ethinyl magnesium chloride produces the enamine ofFormula IV. Subsequent splitting of the enamine leads tolfl-amino-estr-4-ene-3-ones, 17tX-Sllb5titllt6d steroids (R =CH C H-CH=CH -CECH). In analogous manner, by starting withIOfl-amino-Sa-hydrogen estrane- 3,17-dione (Ia) according to processscheme IV, the fl-amino-Sa-hydrogen-estrane-l7fi-ol-3-one and the17msubstituted derivatives thereof (Vla) are obtained (R =CH C2H5, HC CHScheme IV:

The same compounds are obtained by starting with compounds of thefollowing formula if at 8 wherein R R R and z have the same meaning asset forth hereinbefore and wherein C-S has the a configuration when zrepresents a single bond.

This reaction is shown in reaction scheme V below HQN which illustratesthe acid chloride formation, its conversion to for example azide andfinally the Curtius rearrangement to yield 1018-amino-ster0ids.

Another manner of obtaining the same products starts with compounds ofthe formula:

R1 I H? 5 0:0 l

and is illustrated by reaction scheme VI Scheme VI:

wherein the formation of mixed lOfi-carboxy-anhydride, the conversionthereof to, for example, lOfi-carbonylazide and finally therearrangement to IOB-isocyanato derivative, and then the passage toIOB-amino steroid occurs.

Reaction of B-amino-ester-4-ene-3-ones of the following formula whereinR, R and R have the same meaning as set forth hereinbefore, withalcohols such as anhydrous methanol or ethanol in the presence of acidssuch as hydrogen chloride, p-toluenesulfonic acid, sulfonic acid,trichloroacetic acid,

trifluoracetic acid allows the preparation of compounds of the formulawherein R, R and R have the same meaning as set forth hereinbefore and Ris methoxy or ethyoxy.

These compounds are also obtained by applying the reaction Scheme IV tothe compounds of the formula wherein R is methoxy or ethoxy as shown inreaction LiAlH4 NaBlL l// \\RiMgBr Scheme VII:

From the above described 10fi-amino-estra-li,5-diene-3- enolethers, byreaction with 2,3-dicyan-5,6-dichloro-benzoquinone in a solvent such asbenzene, dioxane, acetone, water or mixtures thereof according to thefollowing reaction scheme,

HgN HzN can a the corresponding 10B-amino-estra-4,6-diene-3-ones of thefollowing formula are obtained:

wherein R, R and R have the same meaning as set forth hereinbefore.

The following non-limitative examples illustrate the in vention:

EXAMPLE 1 10fl-isocyanato-l9-nor-androst-5-ene-3,17-diacetate To 8.660parts of IO-Q-carboxy-19-nor-androst-5-ene- 3,17-diacetate dissolved in900 parts anhydrous benzene were added 18 parts of thionyl chloride andthe mixture was allowed to reflux for 8 hours, then evaporated todryness and the thionyl chloride was removed by 3 successivedistillations with anhydrous benzene to obtainlOfl-chloroformyl-l9-nor-androst-5-ene-3,l7-diacetate.

The obtained product was dissolved in 160 parts anhydrous acetone and 3parts sodium azide were added. Stirring was continued for 3 hours.Acetone was cold distilled and then the product was diluted with water.The product did not crystallize therefore it was extracted with ethylether, dehydrated with sodium sulfate and evaporated to dryness toobtain the lOfi-carbonylazide- 19-nor-androst-5-ene-3,l7-diacetate. Theproduct showed under LR. spectrum analysis the characteristic band ofazide: 2120 cm-.

parts toluene were added to the residue and it was allowed to stand on asteam bath for 2 hours. By evaporation to dryness,IOB-isocyanato1'9-nor-androst-5- ene 3,17 diacetate was obtained: LR.2220 cm.- (N=(:O).

1 1 EXAMPLE 2 10p-isocyanato-19-nor-androst-5-ene-3-acetate-17-one Byoperating as described in Example 1, but starting withIOB-carboxy-19-nor-androst-5-ene-3-acetate-l7-one,IOB-isocyanato-19-nor-androst-5-ene-3-acetate-17-one was obtained.

EXAMPLE 3 1OB-amino-19-nor-androst-5-ene-1,17-diacetate 5.6 parts oflfi-isocyanato-l9-nor-androst-5-ene-3,17- diacetate were suspended in100 parts of 50% acetic acid. The mixture was allowed to stand on asteam-bath for 2 hours, then concentrated under vacuum to dryness andthen diluted with water. After extraction with ethyl acetate, theproduct was washed with 10% sodium bicarbonate and then with water untilneutrality. The product was then dehydrated on sodium sulfate andevaporated to dryness. The product crystallized from ethyl ether toaflord parts of 1OB-amino-19-nor-androst-5-ene-3,17- diacetate which hada M.P. of 166168 C. and a a (OHCI of --102.

EXAMPLE 4 1OQ-amino-19-nor-androst-5-ene-3-acetate-17-one Operatingsimilarly to Example 3, from IOB-isocyanato-19-nor-androst 5ene-3-acetate 17 one, fi amino-19-nor-androst-5-ene-3-acetate-17-one wasobtained which had a M.P. of 181182 C. and a 0: (CHCl of 35.

EXAMPLE 5 IOB-carbomethoxyamino-19-nor-androst-5-ene-3,17- diacetate 1.5parts of 10,8-isocyanato-19-nor-androst-5-ene-3,17- diacetate arerefluxed in methanol for 3 hours, then evaporated to dryness to obtain aproduct under oily form. A separation is carried out on silica-gelcolumn, by employing 50 parts silicagel, while eluating with methylenechloride. Finally 0.050 part10fi-urethane-19-norandrost-5-ene-3,17-diacetate are obtained; M.P. 178-180 C.; LR. 1530 cm? (urethane).

EXAMPLE 6 10 3-amino-19-nor-androst-5-ene-3,17-diol One part oflOB-amino-10-nor-androst-S-ene-3,17-diacetate in 24 parts of methanolicKOH is allowed to reflux for one hour. The product was then evaporatedto dryness, neutralized with monosodium phosphate and extracted 5 timeswith ethyl acetate. The combined organic phases were washed with alittle salt water, dehydrated with sodium sulfate and evaporated todryness to afford 0.75 part of IOB-amino-19-nor-androst-5-ene-3,17-di0l.

EXAMPLE 7 '105-amino-19-nor-androst-5-ene-3/3-ol-17-one In a mannersimilar to Example 6, while starting with IOfl-amino 19nor-androst-5-ene-3-acetate-17-one, 10B-amino-l9-nor-androst-5-ene-3fl-ol 17 one was obtained; M.P. 178-179 C.;a (CHCl )=45.

EXAMPLE 8 10p-amino-19-nor-androst-4-ene-3,17-dione 0.7 part of1OB-amino-l9-nor-androst-5-ene-3,17-diol were suspended in 130 partstoluene and 6.5 parts cyclohexanone. 25 parts toluene were slowlydistilled and then 1.2 parts aluminum isopropylate in 18 parts toluenewere added within minutes under stirring. The mixture was allowed toreflux for 16 hours, then cooled and then 3.8 parts Seignette saltdissolved in 5.4 parts water were slowly added. Stirring was continuedfor 15 minutes and the two layers separated. The organic phase afterwater washing was set aside and the aqueous phase, reepatedly washedwith benzene, was discarded. The combined organic phases weresteam-distilled. The residue was extracted with methylene chloride toobtain 0.35 part of amino-l9-nor-androst-4-ene-3,17-dione; M.P. 196- 199C.; x =234 m 6: 14,500.

EXAMPLE 9 10fi-amino-3-ethoxy19-nor-androsta-3,5-diene-17-one 0.3 partof IOfl-amino-19-nor-androst-4-ene-3,l7-dione were dehydrated withbenzene and dissolved in 1.6 parts anhydrous dioxane. 0.18 partp-toluene sulfonic acid (dehydrated in benzene) were added. When thewhole mass was in solution, 0.4 part freshly distilled triethylorthoformate were added as well as 0.27 part of a solution of thefollowing composition: 0.244 part p-toluenesulfonic acid, 2.7 partsanhydrous dioxane and 0.55 part absolute ethanol. The reaction mixturewas left at room temperature for 14 hours and then 10 parts of watercontaining 0.4 part sodium bicarbonate were added. The mixture was thenevaporated to dryness and extracted several times with methylenechloride. The residue was washed with salt water, dehydrated on sodiumsulfate and evaporated to dryness.

The product crystallized from ethyl ether, yielding 0.170 part of 105amino-3-ethoxy-19-nor-androsta-3,5- diene-17-one; M.P. 172-175 C.; A(ethanol)=243 III/1.; e=21,500; LR. 1740 cm? (17-ketone); 1655, 1628 cm.(3-ethoxy-3,5-diene).

EXAMPLE 10 1OB-amino-3-N-pyrrolidyl-19-nor-androsta-3,5- dienel 7-one0.25 part of IOfl-amino-19-nor-androsta-3,S-diene-17- one were refluxedin 15 parts benzene in the presence of a marcusson. After 15 minutes,0.015 part p-toluenesulfonic acid were added, then, after half an hour,1.25 parts pyrrolidine. The mixture was allowed to reflux for 12 hours,then cooled and washed with a cold sodium carbonate solution and thenwith Water to neutrality. The residue was dehydrated on sodium sulfateand evaporated to dryness. 0.3 part of product were obtained which werechromatographed on basic alumina to afford 0.165 part 1013amino-3-N-pyrro1idyl-19-nor-androsta-3,5-diene-l7- one; M.P. 141-143 C.A :275 m e=l8,750.

EXAMPLE 11 IOB-amino-19-nor-tetosterone 0.3 part of10fi-amino-Z-N-pyrrolidyl-19-nor-androsta- 3,5-diene-17-one weredehydrated in benzene and dissolved in 20 parts anhydroustetrahydrofurane. 0.45 part lithium aluminum hydride Were added, and themixture was kept under stirring for 2 hours at room temperature. Asaturated sodium sulfate solution was added dropwise. Diluting withethyl acetate resulted in the formation of two phases. The aqueous phasewas extracted with ethyl acetate and the combined organic phases werewashed with water to neutrality. The product was dehydrated on sodiumsulfate and evaporated to dryness to obtain 0.3 part of 10,8amino-3-N-pyrrolidyl-19-nor-androsta-3,5- diene-17-ol (I.R.:disapperance of 17-'ketone band). The product was treated withoutfurther isolation with 6 parts methanol, 0.82 part sodium acetate, 0.82part water and 0.64 part glacial acetic acid. It was left to reflux on awater bath for 4 hours and then evaporated to dryness and extracted withethyl ether. The residue was washed with salt water to neutrality, thenwith a little distilled water. The product was dehydrated and evaporatedto dryness and crystallized from ethyl ether to afford 0.18 part ofIOB-amino-19-nor-testosterone; M.P. -5 C a =+ll3 (CHCl )t =223 m(ethanol);

e:ll,520

13 EXAMPLE 12lOfi-amino-l9-nor-androst-5-ene-3(3-01-17,8-hydroxyl7a-methyl 0.7 partof 10/i-amino-19-nor-androst 5 ene-3-,B-ol 17-one in 30 parts anhydrousbenzene were treated with 20 parts ethereal methylmagnesium bromidesolution. The mixture was refluxed for two hours, then cooled and theexcess reagent was decomposed with an ammonium chloride solution. Theorganic phase was extracted with ethyl acetate and washed with asaturated salt solution. 0.5 part raw product were obtained whichcrystallized from acetone to afford 10,8-amino-19-nor-androst 5ene-3B-ol-17flhydroxyalh-methyl; M.P. 221-223 C.; oc =1l9 (dioxane).

EXAMPLE 13 10fl-amino-19-nor-androst-5-ene-3p-ol 17/3-ol-17a-ethyny10.75 part of 10fi-amino-19-nor-androst 5 ene-3 8-0l- 17-one weredissolved in 70 parts anhydrous tetrahydrofurane. The solution was keptat C. for half an hour in a nitrogen stream, then for 30 minutespurified acetylene is bubbled thereinto. Within 15 minutes, 13 parts ofa solution of the following composition were added: 0.75 part potassiumin 17.5 parts tert. butyl alcohol. The mixture was kept in an acetylenestream for 6 hours and overnight in a refrigerator. The precipitate wasfiltered and dried under vacuum and then it was suspended in a saturatedammonium chloride solution and filtered. 0.570 part IOfi-amino 19nor-androst ene-3B-o1-17B-ol- 17a-ethynyl were obtained; oc =160(dioxane); M.P. varied from one sample to another, owing certainly todifferent crystalline forms. The ascertained M.P. were: 212213.50 C.;185188 C.; 160-166" C. All products are unitary and corresponded witheach other after thin layer chromatographic examination.

EXAMPLE 14 10,8-amino-19-nor-androst-5-ene-3fl,17,8- diO1-17ot-Vinyl Bystarting with IOB-amino .19 nor-androst-S-ene- 3fl-ol-17-one andemploying vinylmagnesium chloride and operating as described in (Example13) B-amino-19- nor-androst 5 ene-3{3,l7fi-diol-17oc-viny1 was obtained;M.P. 197200 C.

EXAMPLE 15 1OB-amino-l9-nor-androst-4-ene-3-one- 1773-01- 17u-ethyny10.6 part of dehydrated 10,8-amino-l9-nor-androst-5-ene-3B,l7,6-diol-17a-ethynyl were warm dissolved in 2 parts dioxane, 38parts anhydrous toluene and 6.4 parts cyclohexanone.

15 parts of solvent were distilled within 30 minutes and 0.6 partaluminum isopropylate dissolved in 6 parts anhydrous toluene were addeddropwise within 15 minutes. The mixture was allowed to reflux for 5hours, then cooled and 20 parts of saturated solution of Seignette saltwere added. The aqueous phase was extracted and distilled in a steamstream. It was extracted with methylene chloride, washed with a littlewater and evaporated to dryness. The product was crystallized fromisopropyl alcohol to obtain 0.3 part 10,8-amino-19-nor-androst-4-ene-3-one-l7B-ol-17a-ethynyl; M.P. 263 265 C.; a =+31.5 (dioxane); A(ethanol)=234 III/1.; e=13,150.

EXAMPLE 16 10fl-amino-l9-nor-l7a-methyl-testosterone By starting with10,8-amino-19-nor-androst 5 ene- 3/3,17,B-diol-17a-methyl and proceedingas in Example 15, lOfl-amino 19 nor-androst-4-ene 3one-17/3-ol-l7amethyl was obtained; M.P. 177179 C.; oc =+79 C.(chloroform); A =235 mu (ethanol); e=12,800.

1 4 EXAMPLE 17 IOfl-amino-l9-nor-androst-4-ene-3-one- 176-01- l7a-vinylBy starting with 10,8-amino-19-nor-androst 5 ene- 36,17fl-diol-l7a-vinyl and proceeding as described in Example 15,1OB-amino-19-nor-androst-4-ene 3 one-17B- O1-170t-Vil'1y1 was obtained;M.P. 200203 C.; a =55 C.; A =234 III/1.; e=13,090.

EXAMPLE 18 l0fi-carboxyl9-nor-androstane-3,l7-diacetate 0.750 part of10fl-carboxy-l9-nor-androst 5 ene-3,17- diacetate were dissolved in 20parts ethanol and 0.150 part platinum oxide were added. The mixture wasstirred for one hour during which an adsorption of 70 parts hydrogenoccurred. Catalyst was filtered off, and the product was evaporated todryness and crystallized from ethyl ether. 0.4 part 10,8-carboxy 19nor-androstane-3,17- diacetate were obtained; M.P. 207-208 C.; oc =55(chloroform) EXAMPLE 19 10fi-carbamoyll9-nor-a-androstane-3,17-diacetate To 0.4 part of IOB-carboxy-19-nor-androstane-3,17-diacetateat 0 C., 1.6 parts thionyl chloride were added and the mixture was keptat 0 C. for half an hour and for 3 hours at room temperature. Themixture was evaporated to dryness and then 10 parts 28% aqueous ammoniawere added and the mixture was stirred for one hour. The product wasevaporated to dryness and extracted with ethyl ether. It was then washedto neutrality, dehydrated and evaporated to dryness. The product wascrystallized from ethyl ether to yield 0.25 part ofIOB-carbamoyl-19-nor-androstane-3,17-diacetate; M.P. 188- 190 C.; a =-76(chloroform).

EXAMPLE 20 10fi-amino-19-nor-androstane-3, l 7-diacetate 1.5 parts of1OB-carboxy-l9-nor-androstane-3,17-diacetate in 150 parts anhydrousbenzene were refluxed with 3 ml. thionyl chloride for 4 hours. Themixture was evaporated to dryness and combined again several times withbenzene. The obtained acid chloride was dissolved in 30 parts anhydrousacetone and 0.55 part sodium azide were added at 0 C. The mixture wasallowed to stand at 0 C. for half an hour, then for 3 hours at roomtemperature. After concentration, it was diluted with water, extractedwith ether and washed with water until neutrality. The solution was thendehydrated and evaporated to dryness. LR. spectrum shows that a greatpart of the product is under the form of10fi-carbonylazide-19-nor-androstane- 3,17-diacetate. To the obtainedproduct, parts toluene were added, keeping the mixture for one hour on awater bath. The mixture was evaporated to dryness to obtain 10Bisocyanato 19 nor androstane 3,17 diacetate (LR. 2260 cm. N:C=O).

This product was warm dissolved in 100 parts of a 50% acetic acidsolution and kept for 3 hours on a water bath. After evaporation todryness, the LR. spectrum did not show the isocyanato band. The productwas subjected to chromatography on silicagel to obtain 0.3 part ofarnino-l9-nor-androstane-3,l7-diacetate; M.P. 162164 C. a =81(chloroform).

EXAMPLE 21 IOB-isocyanato-19-nor-testosterone-17B-propionate 2 parts of10fi-carboxy-19-nor-androst-4-ene-3-one-175- propionate were dissolvedin 100 parts acetone and 0.6 part water and 8.4 parts of a solutionconsisting of 1.14 parts triethylamine and 10 parts acetone as well as8.4 parts of a solution consisting of 0.86 part ethyl chlorocarbonateand 10 parts acetone were added at 0 C. The mixture was allowed to standfor 30 minutes at 0 C., thereafter 0.6 part sodium azide in 5 partswater were added, keeping the mixture at C. for 2 hours. The product wasdiluted with water, extracted with ethyl ether, washed with water,dehydrated and evaporated to dryness. 1.3 parts of10fi-carbonylazide-19-nor-androst-4-ene-3-one-l7- propionate wereobtained (LR. 2120 CHI-1! N which were dissolved in 100 parts tolueneand kept for two hours on a water bath until small bubbles wereproduced. It was then evaporated to dryness to obtain 1.05 parts of 105-isoeyanato-19-nor-testosterone-l7fi-propionate. The obtained product wassubjected to chromatography on silicagel column and, by elution With amixture of hexane and methylene chloride (8:2), 0.6 part of10,8-isocyanato-19- nor-testosterone-17fi-propionate were obtained; M.P.82- 85 C.; a =+l54 C. (chloroform).

0.5 part of IOB-isocyanato-l9-nor-testosterone-17fl-propionate weredissolved in 50 parts of 50% acetic acid solution and heated on a waterbath for 2 hours. The mixture was evaporated to dryness. The product didnot crystallize, therefore it was subjected to chromatography onsilicagel and by elution with hexane-ethyl ether (7:3), 0.27 part ofl0/3-amino-19-nor-testosterone-17fl-propionate were obtained; M.P.l25127 C.; a =+l00 (chloroform); X :234 III/1.; 13,800.

EXAMPLE 23 l0fi-propionarnido-19-nor-androst-4-ene-3-one-17/3-propionate 0.2 part of IOB-amino-19-nor-androst-4-ene-3-one-175-propionate were propionylated under the usual conditions to alford 0.2part of IOB-propionamide-19-nor-androst-4- ene-3-one-17/i-propionate;M.P. 232-234 C.; M :248 my; e=12,700.

EXAMPLE 24 l0fl-carbomethoxyamino-l9-nor-androst-4-ene-3-one-17B-propionate 0.5 part of IOB-isocyanato-19-nor-androst-4-ene-3-one-17,8-propionate were refluxed for hours in 50 parts methanol. Themixture was evaporated to dryness and the disappearance of theisocyanate band was ascertained by I.R. spectrum analysis. The productwas subjected to chromatography on silicagel column and eluated withethyl ether/hexane (1:1) to obtain 0.370 part of 1013- urethane 19 norandrost-4-ene-3-one-17fl-propionate; M.P. 172l76 C.; ot :+42 C. (inchloroform); k =239 III/L; 13,500.

EXAMPLE 25 lOfi-ureidol 9-nor-androst-4-ene-3-one- 1 7fi-propionate 0.5part of 10,8-isocyanato-l9-nor-androst-4-ene-3-one- 17,8-propionate weretreated with 200 parts of ammonia for two hours at 0 C. and the ammoniawas allowed to evaporate. The product was subjected to chromatography onsilica-gel to give 0.15 part offl-ureido-19-nor-androst-4-ene-3-one-17,8-propionate; M.P. 220-224 C.

EXAMPLE 26 10,8-amino- 1 9-nor-androsta-4,6-diene-3 ,17-one 1 6 Weclaim: 1. A compound of the formula wherein R is hydrogen, alkanoyl of 1to 10 carbon atoms, cyclopentylacetyl, cyclopentylpropionyl,cyclohexylpropionyl, succinyl, glutaryl, methylsuccinyl, benzoyl,salicylyl, p-arninobenzoyl, phenylpropionyl or phenylacetyl;

R is hydrogen, lower alkyl, alkynyl of the formula CEC-Ra or alkenyl ofthe formula where Ra is hydrogen or lower alkyl;

OR and R together are keto;

R is hydrogen or methyl; and

R is hydrogen, methyl, alkanoyl of 1 to 10 carbon atoms,cyclopentylacetyl, cyclopentylpropionyl, cyclohexylpropionyl, succinyl,glutaryl, methylsuccinyl, benzoyl, salicylyl, p-aminobenzoyl,phenylpropionyl or phenylacetyl, COOR where R is methyl, ethyl, propyl,butyl, cyclohexyl, phenyl or phenylmethylene or CONHR where R ishydrogen, methyl, ethyl, propyl, butyl, cyclohexyl, phenyl orphenylmethylene.

2. The compound of claim 1 wherein R is hydrogen or alkanoyl of 1 to 10carbon atoms and R is hydrogen, methyl, alkanoyl of 1 to 10 carbon atomsor COOR or CONHR where R is methyl, ethyl, propyl or butyl.

3. A compound of the formula 1 TF5 l R30U R is hydrogen, alkanoyl of lto 10 carbon atoms, cyclopentylacetyl, cyclopentylpropionyl,cyclohexylpropionyl, succinyl, glutaryl, methylsuccinyl, benzoyl,salicylyl, p-aminobenzoyl, phenylpropionyl or phenylacetyl;

R is hydrogen, lower alkyl, alkynyl of the formula -CECRa or alkenyl ofthe formula -CH=CHRa wherein Ra is hydrogen or lower alkyl;

OR and R together are keto;

R is hydrogen, formyl, acetyl or benzylcarboyl;

R is hydrogen or methyl;

R is hydrogen, methyl alkanoyl of l to 10 carbon atoms,cyclopentylacetyl, cyclopentylpropionyl, cycylohexylpropionyl, succinyl,glutaryl, methylsuccinyl, benzoyl, salicylyl, p-aminobenzoyl,phenylpropionyl or phenylacetyl or COOR or CONHR where R is methyl,ethyl, propyl, butyl, cyclohexyl, phenyl or phenylmethylene; and

t represents a single or double bond and where the hydrogen atom at C-5has the a configuration when t represents a single bond.

4. The compound of claim 3 wherein R is hydrogen or alkanoyl of 1 to 10carbon atoms and R is hydrogen, methyl, alkanoyl of 1 to 10 carbon atomsor COOR or CONHR where R is methyl, ethyl, propyl or butyl.

wherein 5. A compound of the formula wherein R is hydrogen, alkanoyl ofl to 10 carbon atoms, cyclopentylacetyl, cyclopentylpropionyl,cyclohexylpropionyl, succinyl, glutaryl, methylsuccinyl, benzoyl,salicylyl, p-aminobenzoyl, phenylpropionyl or phenylacetyl;

R is hydrogen, lower alkyl, alkynyl of the formula C- -CRa or alkenyl ofthe formula -CH=CHRa wherein Ra is hydrogen or lower alkyl;

OR and R together are keto';

R is hydrogen or methyl;

R is hydrogen, methyl, alkanoyl of 1 to carbon atoms, cyclopentylacetyl,cyclopentylpropionyl, cyclohexylpropionyl, succinyl, glutaryl,methylsuccinyl, benzoyl, salicylyl, p-aminobenzoyl, phenylpropionyl orphenylacetyl, or COOR or -CONHR where R is methyl, ethyl, propyl, butyl,cyclohexyl, phenyl or phenylmethylene; and

R is methoxy, ethoxy, morpholino, pyrrolidyl or piperidino.

6. The compound of claim 5 wherein R is hydrogen or alkanoyl of 1 to 10carbon atoms and R is hydrogen, methyl, alkanoyl of 1 to 10 carbon atomsor COOR or CONHR where R is methyl, ethyl, propyl or butyl.

7. A compound of the formula wherein RsO- wherein R is hydrogen,alkanoyl of 1 to 10 carbon atoms, cyclopentylacetyl,cyclopentylpropionyl, cyclohexylpropionyl, succinyl, glutaryl,methylsuccinyl, benzoyl, salicylyl, p-aminobenzoyl, phenylpropionyl orphenylacetyl;

R is hydrogen, lower alkyl, alkynyl of the formula CECRa or alkenyl ofthe formula CH=CHRa wherein Ra is hydrogen or lower alkyl;

OR and R together are keto;

R is hydrogen, formyl, acetyl or benzylcarboyl; and

t represents a single or double bond and wherein the hydrogen atom atC-5 has the at configuration when t represents a single bond.

10. The compound of claim 9 wherein R is hydrogen or alkanoyl of l to 10carbon atoms.

11. A compound of the formula wherein R is hydrogen, alkanoyl of 1 to 10carbon atoms, cyclopentylacetyl, cyclopentylpropionyl,cyclohexylpropionyl, succinyl, glutaryl, methylsuccinyl, benzoyl,salicylyl, p-aminobenzoyl, phenylpropionyl or phenylacetyl;

R is hydrogen, lower alkyl, alkynyl of the formula CECRa or alkenyl ofthe formula -CH=CHRa wherein Ra is hydrogen or lower alkyl;

OR and R together are keto;

R is hydrogen, formyl, acetyl or benzylcarboyl;

W is N3, NH2 0r OCOOC2H5, and t represents a single or double bond andwherein the hydrogen atom at C5 has the a configuration when trepresents a single bond.

12. The compound of claim 11 wherein R is hydrogen or alkanoyl of 1 to10 carbon atoms and W is -N -NHOCOC H NH or OCOOC -H 13. A process forthe preparation of a 10 3-amino compound of the formula:

NHZ

wherein R is hydrogen, lower alkyl, alkyne of the formula C CRa 0ralkene of the formula CH=CHRa wherein Ra is hydrogen or lower alkyl;

R and R together are keto,

bond, comprising reacting a compound of the formula:

R t? HO-C or an alkali metal salt thereof wherein R R R R and t are asdefined with respect to said 105- amino compound and wherein C-S has thea configuration when t represents a single bond with thionyl chloride,oxalyl chloride, PCl or P0Cl in a solvent selected from the groupconsisting of henzene, ether, hexane and dimethylformamide, reacting theresulting product with an alkali metal azide,

ammonia or hydroxylamine and benzoyl chloride and placing the resultingproduct in a medium selected from the group consisting of benzene,water, acetic acid, hydrochloric acid, ether and mixtures thereof toform said l0 3-amino compound. 14. A process for the preparation of a10fl-amino compound of the formula:

wherein R is hydrogen, lower alkyl, alkyne of the formula CECRa oralkene of the formula CH=CHRa wherein Ra is hydrogen or lower alkyl; Rand R together are keto,

R is hydrogen or lower alkyl; and

z represents a single or double bond and wherein C-5 has the onconfiguration when z represents a single bond, comprising reacting acompound of the formula:

..R a MR8 no or an alkali metal salt thereof wherein R R R and z are asdefined with respect to said lOfi-amino compound and wherein C-S has thea configuration when z represents a single bond with thionyl chloride,oxalyl chloride, PCl or P0013 in a solvent selected from the groupconsisting of benzene, ether, hexane and dimethylformamide, reacting theresulting product with an alkali metal azide, ammonia or hydroxylamineand benzoyl chloride and placing the resulting product in a mediumselected from the group consisting of benzene, water, acetic acid,hydrochloric acid, ether and mixtures thereof to form said IOfl-aminocompound.

15. A process for the preparation of a l0/3-amino compound of theformula:

wherein R is hydrogen, lower alkyl, alkyne of the formula CECR3. oralkene of the formula CH=CHRa wherein Ra is hydrogen or lower alkyl;

R and R together are keto,

R is hydrogen, formyl, acetyl or benzylcarboyl;

R is acyloxy where the acyl group is derived from a saturated aliphaticcarboxylic acid containing 1 to 10 carbon atoms, cyclopentylacetic acid,cyclopentylpropionic acid, cyclohexylpropionic acid, succinic acid,glutaric acid, methylsuccinic acid, benzoic acid, salicylic acid,p-aminobenzoic acid, phenylpropionic acid or phenylacetic acid;

R is hydrogen or lower alkyl; and

t represents a single or double bond and wherein C-S has the aconfiguration when t represents a single bond, comprising reacting acompound of the formula:

wherein R R R R and t are as defined with respect to said l05-aminocompound and wherein C-S has the a configuration when t represents asingle bond with ethyl chlorocarbonate or an acid of the formula R COOHwherein R is methyl, ethyl, propyl, butyl, cyclohexyl, phenyl orphenylmethylene in a solvent selected from the group consisting ofacetone, tetrahydrofurane, dioxane, benzene or dimethylformamide to forma 10,6-carboxyanhydride compound of the formula:

ing of benzene, toluene and ether to form a 10,8-isocyanato compound ofthe formula:

wherein R is hydrogen, lower alkyl, alkyne of the formula CECRa oralkene of the formula -CH=CHRa wherein Ra is hydrogen or lower alkyl;

R, and R together are keto,

R is acyloxy where the acyl group is derived from a saturated aliphaticcarboxylic acid containing 1 to 10 carbon atoms, cyclopentylacetic acid,cyclopentylpropionic acid, cyclohexylpropionic acid, succinic acid,glutaric acid, methylsuccinic acid, benzoic acid, salicyclic acid,p-aminobenzoic acid, phenylpropionic acid or phenylacetic acid;

R is hydrogen or lower alkyl; and

z represents a single or double bond; and wherein C5 has the occonfiguration when z represents a single bond, comprising reacting acompound of the formula:

wherein R R R and z are as defined with respect to said 10,8-aminocompound and wherein C-S has the a configuration when z represents asingle bond with ethyl chlorocarbonate or an acid of the formula R COOHwherein R is methyl, ethyl, propyl, butyl, cyclohexyl, phenyl orphenylmethylene in a solvent selected from the group consisting ofacetone, tetrahydrofurane, dioxane, benzene or dimethylformamide to forma IOB-carboxyanhydride compound of the formula:

0 0 II II o-o- 0-51 wherein R R7, R and z are as defined with respect tosaid 10,8-amino compound and wherein C-S has the a configuration when zrepresents a single bond and placing said lOfl-isocyanato compound in amedium seelcted from the group consisting of water, acetic acid,hydrochloric acid, ether and mixtures thereof to form said lOB-aminocompound.

References Cited UNITED STATES PATENTS 10/1966 Bowers 260397.4 12/1968Knox 26O397.1

ELBERT L. ROBERTS, Primary Examiner U.S. Cl. X.R.

